Elevated echocardiographic pulmonary to left atrial ratio (ePLAR) in high-altitude residents

Introduction

Globally, approximately 400 million people reside at altitudes above 1,500 meters, with over 100 million lowlanders visiting areas above 2,500 meters annually (1). This study focuses on permanent residents at extreme altitudes (≥4,000 meters), a distinct population with profound physiological adaptations. Residents at such high altitudes are chronically exposed to hypoxic conditions. This exposure can induce hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling, ultimately leading to elevated pulmonary arterial pressure (2). Concurrently, sympathetic activation, blood flow redistribution, and increased systemic blood pressure may also occur. These hemodynamic changes can further contribute to alterations in left ventricular diastolic function and left atrial pressure (1). As a result, the trans-pulmonary gradient—defined as the difference between pulmonary artery pressure and left atrial pressure—may differ in this population compared to lowland residents.

Accurate hemodynamic classification and precise differentiation of pulmonary hypertension are crucial for clinical diagnosis and treatment. Distinguishing between pre-capillary and post-capillary pulmonary hypertension directly influences therapeutic decision-making and prognosis assessment. The echocardiographic pulmonary to left atrial ratio (ePLAR), first introduced by Scalia et al. in 2016, is an emerging non-invasive parameter that reflects the trans-pulmonary gradient and helps to differentiate pre-capillary from post-capillary pulmonary hypertension (3). In recent years, ePLAR has been applied to evaluate hemodynamic and cardiac functional changes under various physiological and pathological conditions such as exercise, pulmonary hypertension, pulmonary embolism, and the coronavirus disease of 2019 (COVID-19), and has also been used for prognostic assessment (4-7).

However, established reference ranges for ePLAR across different populations remain limited, and studies specifically aimed at defining normal ePLAR reference values for high-altitude residents are particularly lacking. Therefore, this study aimed to systematically assess ePLAR values in healthy high-altitude residents to establish population-specific reference ranges. The findings are expected to provide a scientific basis for early screening, accurate phenotyping, and individualized management of pulmonary hypertension in high-altitude populations. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2111/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Human Research Ethics Committee of Yangpu Hospital, School of Medicine, Tongji University (No. LL-2024-SHZRKX-001). Written informed consent was provided by all participants prior to enrollment. The consent form detailed the study procedures, including and blood sampling, along with their purpose, potential risks, and benefits. All participant data were anonymized using unique study IDs and stored on password-protected, encrypted hospital servers accessible only to the research team. Between July 2024 and June 2025, consecutive healthy adult (aged 18–75 years) high-altitude residents (≥4,000 meters above sea level) with ≥3 consecutive generations of altitude residence who had no symptomatic complaints or detectable physical signs, were enrolled from routine health screening camps conducted during a medical support mission in Lhatse County, Shigatse City, Tibet Autonomous Region, China (average altitude ~4,500 meters). Age- and sex-matched low-altitude controls (≤5 meters) were recruited from health check-ups at our institution in Shanghai, China. All the participants underwent comprehensive diagnostic evaluation, as follows: (I) systematic review of cardiopulmonary history, (II) thorough physical examination, (III) laboratory investigations (including tumor markers and myocardial enzymes), (IV) electrocardiography, and (V) multimodality imaging (radiography, ultrasonography, and computed tomography). Participants with abnormal findings suggestive of cardiopulmonary or systemic disease, even in the absence of prior diagnosis or treatment, were excluded. The exclusion criteria encompassed the following: (I) confirmed cardiopulmonary or systemic pathologies (hypertension, pulmonary hypertension, diabetes, hyperlipidemia, cardiac dysfunction, atrial fibrillation, or > mild valvular disease); (II) smoking; (III) current use of cardiorespiratory medications, chemotherapeutic agents, or vasoactive drugs; and (IV) suboptimal echocardiographic image quality per standard guidelines.

Data collection

Age, sex, body mass index (BMI), resting systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and precise residential altitude were recorded. Fasting venous blood was analyzed for hemoglobin concentration.

Transthoracic echocardiography

All transthoracic echocardiography examinations were performed by two experienced radiologists, each with over 20 years of clinical expertise, using an EPIQ 7C ultrasound system (Philips, Amsterdam, Netherlands) equipped with an X5-1 PureWave xMATRIX transducer (1–5 MHz). Examinations for high-altitude residents were conducted at their resident altitude (≥4,000 m) using a mobile system, whereas examinations for lowland controls were performed at sea level. The examinations adhered to the latest European Association of Cardiovascular Imaging/American Society of Echocardiography (EACVI/ASE) recommendations (8-10), and the following parameters were acquired: left ventricular end-diastolic anteroposterior diameter (D_LV), right ventricular end-diastolic anteroposterior diameter (D_RV), left atrial end-systolic transverse diameter (D_LA), right atrial end-systolic transverse diameter (D_RA), left ventricular ejection fraction (LVEF), left ventricular mass index (LVM index), right ventricular free wall thickness (FWT_RV), peak tricuspid regurgitation velocity (TRV_max), the ratio of peak early diastolic transmitral filling velocity to peak early diastolic septal mitral annulus tissue velocity (E/e’), velocity-time integral at the right ventricular outflow tract (VTI_RVOT), and tricuspid annular plane systolic excursion (TAPSE). Based on the acquired data, key hemodynamic parameters were derived. The estimated pulmonary artery systolic pressure (PASP) was calculated as: PASP (mmHg) = 4 × (TRV_max)² + right atrial pressure (9). Pulmonary vascular resistance (PVR) was determined using the validated formula: PVR (Wood unit) = (TRV_max/VTI_RVOT)×10+0.16 (11). Finally, the ePLAR, which assesses the relationship between right ventricular systolic pressure and left atrial pressure, was computed. The ePLAR (m/s) was calculated using the formula: ePLAR (m/s) = TRV_max/(E/e’) (3) (Figure 1).

Figure 1 Measurement of TRV_max (A), peak early diastolic transmitral filling velocity (E) (B) and peak early diastolic septal mitral annulus tissue velocity (e’) (C), used to illustrate the calculation method for ePLAR (D) in a low-altitude resident. ePLAR, echocardiographic pulmonary to left atrial ratio; TRV_max, peak tricuspid regurgitation velocity.

Statistical analysis

The distribution of continuous variables was evaluated using the Shapiro-Wilk test. Normally distributed data were expressed as mean ± standard deviation (SD) and compared using independent samples t-tests. For variables violating normality assumptions (confirmed by both Shapiro-Wilk tests and Q-Q plot visualization), non-parametric analyses were employed, with data presented as median with interquartile range (IQR) and compared using Mann-Whitney U tests. Categorical variables were summarized as counts (percentages) and analyzed with chi-square tests. The Kruskal-Wallis test was employed to compare ePLAR across subgroups of high-altitude residents. Multiple linear regression analysis was performed to determine independent determinants of ePLAR in high-altitude residents. A two-tailed P value <0.05 defined statistical significance. All analyses were conducted using the software SPSS 19.0 (IBM Corp., Armonk, NY, USA) and MedCalc 16.8.4 (MedCalc Software, Ostend, Belgium), with graphical assessments performed on both platforms.

Results

Characteristics of included participants

Between July 2024 and June 2025, 120 high-altitude residents and 120 low-altitude residents who met the inclusion criteria completed transthoracic echocardiography. Adequate data, including TRV_max and mitral annular E/e’, were successfully acquired in all participants. As shown in Table 1, high-altitude residents demonstrated markedly elevated hemoglobin concentrations compared to their low-altitude counterparts (P<0.0001). No statistically significant differences were observed between the two cohorts in age, gender distribution, or BMI (P>0.05). High-altitude residents had significantly elevated SBP and DBP, but a reduced heart rate compared to low-altitude residents (P<0.0001 for all).

Echocardiographic assessment revealed enlarged cardiac chamber dimensions (P<0.0001) and increased FWT_RV (P<0.0001) in the high-altitude group. However, LVM index did not differ significantly between groups (P>0.05). High-altitude residents exhibited reduced LVEF and TAPSE (P<0.0001), whereas PASP and PVR were substantially elevated (P<0.0001). The high-altitude group demonstrated significantly greater TRV_max and lower mitral E/e' ratio, collectively resulting in a significantly higher ePLAR value compared to the low-altitude group (P<0.0001).

Subgroup analyses conducted within the high-altitude population, stratified by sex, age, BMI, SBP, and hemoglobin levels, revealed significant differences in ePLAR values across BMI and SBP subgroups (P<0.01) (Table 2). Specifically, higher BMI and elevated SBP were inversely correlated with ePLAR values.

Multiple linear regression analysis

As shown in Table 3, BMI, SBP, and TAPSE each demonstrated statistically significant correlations with ePLAR in the multiple regression analysis using the enter method (P<0.05). In the stepwise multiple regression analysis, TAPSE, hemoglobin, age, gender, BMI, and SBP were all identified as independent determinants of ePLAR (P<0.05; Table 4). The resulting optimal regression model was as follows: ePLAR =0.826–0.014 × TAPSE + 0.001 × hemoglobin + 0.002 × age – 0.054 × gender (female =0, male =1) – 0.006 × BMI – 0.002 × SBP (R=0.448; R²=0.201; adjusted R²=0.186; F=13.80; P<0.0001).

Intra-/inter-observer variability

To assess measurement reliability, intraobserver and interobserver variability analyses were conducted. For intraobserver consistency, Observer A repeated TRV_max, E, and e’ measurements in 30 randomly selected cases after a 3-week interval to reduce recall bias, demonstrating exceptional reproducibility with an intraclass correlation coefficient (ICC) of 0.98 [95% confidence interval (CI): 0.98–0.99] and a coefficient of variation (CV) of 1.7–2.3%. Interobserver agreement was evaluated by having two independent observers (Observer A and B) analyze the same 30 cases, revealing strong concordance with an ICC of 0.97 (95% CI: 0.97–0.99) and a CV of 1.9–2.5%. These results confirm high measurement consistency both within and between observers.

Discussion

This study provides the first systematic analysis demonstrating that healthy long-term residents of high-altitude regions exhibit significantly higher ePLAR values compared to their low-altitude counterparts. This finding aligns with established principles of high-altitude physiology, wherein chronic hypoxic exposure triggers hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling, which are primary mechanisms leading to elevated pulmonary arterial pressure. Notably, the increase in ePLAR reflects a proportionally greater rise in PASP relative to the change in left atrial pressure. This observation is consistent with the original purpose of ePLAR, as proposed by Scalia et al., for differentiating pre-capillary from post-capillary pulmonary hypertension (3). Our research extends the application of ePLAR from disease differential diagnosis to the realm of high-altitude physiological adaptation, offering a novel perspective for understanding the unique cardiopulmonary hemodynamic profile of high-altitude populations.

Our investigation identified TAPSE, hemoglobin, age, sex, BMI, and SBP as independent determinants of the ePLAR value. This multifactorial association underscores the complexity of cardiopulmonary circulatory adaptation in high-altitude environments. The correlation between TAPSE, a marker of right ventricular function, and ePLAR highlights the critical importance of right ventricular-pulmonary circulation coupling in high-altitude adaptation, echoing recent perspectives on high-altitude cardiovascular health put forth by Mallet et al. (1). The positive correlation between hemoglobin levels and ePLAR reflects the impact of hemorheological changes on the pulmonary circulation, as chronic hypoxia-induced secondary polycythemia increases blood viscosity and, consequently, elevates PVR (2,12). Furthermore, the associations with demographic and metabolic factors such as age, sex, BMI, and SBP indicate that ePLAR values are influenced by the integrated physiological status of multiple body systems.

Compared to studies conducted in low-altitude populations, the determinants of ePLAR identified in our high-altitude residents exhibit distinct characteristics. In lowland populations, ePLAR is primarily applied for the differential diagnosis of pulmonary hypertension, where its value is influenced by both left heart dysfunction and pulmonary vascular disease. In contrast, the elevated ePLAR values in high-altitude residents likely reflect a more complex interaction between physiological adaptation and pathological changes, potentially related to genetic adaptation mechanisms (such as EPAS1 gene variants) unique to native high-altitude populations (13-15). Our findings emphasize the necessity of establishing high-altitude-specific ePLAR reference ranges, which aligns with the prevailing trend of developing localized reference values for different populations.

Establishing high-altitude-specific ePLAR reference ranges holds significant clinical application value. Firstly, it can provide a quantitative standard for the early screening of pulmonary hypertension in high-altitude areas, aiding in the identification of high-risk individuals with abnormal pulmonary vascular responses who are susceptible to high-altitude pulmonary hypertension. Secondly, in patients who have already developed pulmonary hypertension, the ePLAR reference value can assist in differentiating pre-capillary from post-capillary pulmonary hypertension, thereby guiding subsequent treatment strategies. Furthermore, this reference value can serve as a comprehensive indicator for assessing acclimatization, informing health management strategies for migrants to high altitudes. For instance, in migrants or sojourners, an ePLAR value significantly exceeding the established range might signal excessive pulmonary vascular reactivity and higher risk for altitude illnesses such as high-altitude pulmonary edema. In clinical settings, it could aid in the evaluation of patients presenting with suspected altitude-related cardiopulmonary complications.

Despite these important findings, our study has several limitations. Firstly, the cross-sectional design precludes the determination of causal relationships between ePLAR and the identified factors; future prospective cohort studies are needed to validate these associations. Secondly, the representativeness of our sample may affect the generalizability of the reference values. The genetic and regional heterogeneity within high-altitude populations requires exploration through larger, multi-center studies. The established reference values are primarily applicable to populations residing at extreme high altitudes (≥4,000 m). The generalization to residents at lower high altitudes (e.g., 1,500–2,500 m) should be made with caution and may require separate validation. Additionally, ePLAR relies on echocardiographic measurements, introducing the potential for inter-observer variability, and the study lacked simultaneous validation against the gold standard, right heart catheterization. Future research should aim to address these limitations and define the practical value of ePLAR in predicting and intervening in high-altitude cardiovascular diseases through long-term follow-up.

Conclusions

This study confirms that ePLAR values are significantly elevated in healthy high-altitude residents compared to low-altitude residents. This elevation represents a comprehensive manifestation of multifaceted adaptations within the pulmonary and systemic circulations under chronic hypoxic conditions. The identification of TAPSE, hemoglobin, age, sex, BMI, and SBP as independent determinants reveals the complexity of cardiopulmonary hemodynamic adaptation in high-altitude environments. Establishing a high-altitude-specific ePLAR reference range holds crucial clinical value for the early screening, precise phenotyping, and individualized management of pulmonary hypertension in this population. Although limited by its cross-sectional design, this study provides a fresh perspective for understanding physiological adaptation to high altitude and lays the groundwork for subsequent prospective research.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2111/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2111/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2111/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Human Research Ethics Committee of Yangpu Hospital, School of Medicine, Tongji University (No. LL-2024-SHZRKX-001). Written informed consent was provided by all participants prior to enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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